Treatment with first-line metronomic cyclophosphamide did not significantly improve TTF, PFS, or OS vs doxorubicin in advanced soft tissue sarcoma.
Treatment with metronomic cyclophosphamide did not generate a significant difference in time to treatment failure (TTF), overall survival (OS), and progression-free survival (PFS) compared with standard doxorubicin as a first-line treatment for older patients with advanced soft tissue sarcomas, according to results from the phase 3 METROPHOLYS trial (NCT04656262) presented at the
Among patients who received metronomic cyclophosphamide (n = 21), the median TTF was 10.14 weeks (95% CI, 6.86-15.57); this was not reached (NR) with doxorubicin (n = 18; 95% CI, NR-NR; log-rank P = .26). The median PFS in these respective arms was 2.3 months (95% CI, 2.04-4.01) vs 4.1 months (95% CI, 2.00-9.86; log-rank P = .26). The median OS was 20.90 months (95% CI, 10.25-29.21) vs 19.12 months (95% CI, 6.18-33.35 log-rank P = .87), respectively.
Although these outcomes were not statistically significant, treatment with doxorubicin was associated with a marginal benefit in objective response rate (ORR) and duration of response, albeit with higher rates of toxicities. One patient (6.7%) in the metronomic cyclophosphamide arm achieved a complete response, whereas no partial responses (PR) were observed. In the doxorubicin arm, 4 patients (30.8%) achieved a PR. Progressive disease was the primary reason for treatment discontinuation in both arms (metronomic cyclophosphamide, 81%; doxorubicin 66.7%).
“Despite multicenter collaboration, the study was closed for accrual [due to] futility,” Antonella Brunello, MD, explained in the presentation of the data. “[However], it achieved valued prospective evidence of chemotherapy activity and toxicity in a population of true older patients with soft tissue sarcomas.”
Brunello is a medical doctor at Istituto Oncologico Veneto in Padova, Italy.
Brunella noted that there is a lack of data regarding the treatment of patients aged 70 years or older with metastatic sarcoma. Although doxorubicin is the standard first-line treatment for this population, it is often not feasible for use in older patients and is linked to higher rates of toxicity. Investigators hypothesized that metronomic cyclophosphamide could serve as a less toxic, effective alternative to this standard regimen. The rationale for using metronomic cyclophosphamide included its antineoplastic activity, anti-angiogenic mechanisms, and immune modulation achieved by inhibiting regulatory T cells.
METROPHOLYS was a randomized trial comparing metronomic cyclophosphamide with doxorubicin in patients at least 70 years of age with advanced inoperable or metastatic soft tissue sarcoma who had not previously received chemotherapy for metastatic disease.1,2 Patients needed to have histologically proven disease, at least 1 measurable lesion, an ECOG performance status of 0 to 2, a life expectancy of at least 12 weeks, adequate hepatic function, and normal cardiac function.2
Patients were stratified by G8 score (≤ 14 vs > 14) and histotype (leiomyosarcoma vs other) and were randomly assigned 1:1 to receive either metronomic cyclophosphamide at 50 mg orally once daily or doxorubicin at 60 mg/m2 every 3 weeks for a maximum of 6 cycles.1,2 Of note, patients who were not candidates for randomization were still eligible for the observational study.
The primary end point was TTF. Secondary end points included PFS, OS, ORR, and safety. Translational analyses were also conducted.
Between September 2018 and June 2023, 45 patients were screened and 42 patients were randomly assigned across 8 centers in Italy.1 Patients had a median age of 75 years (range 70-83) in the metronomic cyclophosphamide arm vs 76 years (range 71-86) in the doxorubicin arm. The most common histologies represented were leiomyosarcoma (metronomic cyclophosphamide, 33.3%; doxorubicin, 22.2%) and liposarcoma (23.8%; 44.4%). Most patients had an ECOG performance status of 0 (50%; 55.6%) or 1 (40%; 38.9%). The lung was the most frequent site of metastasis (38.1%; 55.6%). In the metronomic cyclophosphamide arm, the most common site of the primary tumor was retroperitoneal (33.3%); the most common site was the extremities/trunk wall (41.2%) in the doxorubicin arm.
Patients treated with doxorubicin experienced a higher frequency of adverse effects (AEs) compared with those who received metronomic cyclophosphamide. Most patients in the metronomic cyclophosphamide vs doxorubicin arms, respectively, experienced at least 1 AE (66.7%; 88.9%). The incidence of grade 3/4 AEs was 19.0% vs 44.4%, respectively; corresponding rates of grade 3/4 treatment-related AEs were 9.5% vs 33.3%.
Grade 3/4 neutropenia occurred in 6 patients in the doxorubicin arm vs no patients in the metronomic cyclophosphamide arm. Patients who received doxorubicin experienced more grade 1/2 mucositis (n = 7), nausea (n = 6), and diarrhea (n = 3) vs those who received metronomic cyclophosphamide (n = 0; n = 3; n = 1, respectively). Additionally, fatigue was reported in 4 vs 5 patients in these respective arms.
“Though numbers are small and must be interpreted with caution; if the ORR is what we aim for, doxorubicin might be worth a chance,” Brunello concluded. “We found a median OS rate [that was] higher compared with historical data.”
Disclosures: Brunello reported receiving honoraria/advisory board funding from Boehringer Ingelheim, Deciphera, and GSK; as well as receiving coverage of travel expenses from PharmaMar.
